Use of cannabinoids in the treatment of epilepsy

ABSTRACT

The present disclosure relates to the use of cannabidiol (CBD) for the treatment of atonic seizures. In particular the CBD appears particularly effective in reducing atonic seizures in patients suffering with etiologies that include: Lennox-Gastaut Syndrome; Tuberous Sclerosis Complex; Dravet Syndrome; Doose Syndrome; Aicardi syndrome; CDKL5 and Dup15q in comparison to other seizure types. The disclosure further relates to the use of CBD in combination with one or more anti-epileptic drugs (AEDs).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/198,141, filed Nov. 21, 2018, now U.S. Pat. No. 10,849,860, which isa continuation of U.S. patent application Ser. No. 15/449,535, filedMar. 3, 2017, now U.S. Pat. No. 10,137,095, which is a continuation ofSer. No. 14/881,969, filed Oct. 13, 2015, now U.S. Pat. No. 10,111,840which claims priority to GB 1418171.3, filed Oct. 14, 2014. Each ofthese applications is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to the use of cannabidiol (CBD) in thetreatment of atonic seizures. In one embodiment the patients sufferingfrom atonic seizures are children and young adults. CBD appearsparticularly effective in reducing atonic seizures in patients sufferingwith etiologies that include: Lennox-Gastaut Syndrome; TuberousSclerosis Complex; Dravet Syndrome; Doose Syndrome; Aicardi syndrome;CDKL5 and Dup15q in comparison to other seizure types.

In these patients treatment with CBD reduced the occurrence of atonicseizures by greater than 50% in a large proportion, namely 63%, ofpatients. This was surprising given that the proportion of patientsbenefitting from a greater than 50% reduction in total seizures wassignificantly less, (46%), in all subjects treated.

Preferably the CBD used is in the form of a highly purified extract ofcannabis such that the CBD is present at greater than 98% of the totalextract (w/w) and the other components of the extract are characterised.In particular the cannabinoid tetrahydrocannabinol (THC) has beensubstantially removed, to a level of not more than 0.15% (w/w) and thepropyl analogue of CBD, cannabidivarin, (CBDV) is present in amounts ofup to 1%. Alternatively, the CBD may be a synthetically produced CBD.

In use the CBD may be given concomitantly with one or more otheranti-epileptic drugs (AED). Alternatively the CBD may be formulated foradministration separately, sequentially or simultaneously with one ormore AED or the combination may be provided in a single dosage form.Where the CBD is formulated for administration separately, sequentiallyor simultaneously it may be provided as a kit or together withinstructions to administer the one or more components in the mannerindicated. It may also be used as the sole medication, i.e. as amonotherapy.

BACKGROUND TO THE INVENTION

Epilepsy occurs in approximately 1% of the population worldwide,(Thurman et al., 2011) of which 70% are able to adequately control theirsymptoms with the available existing anti-epileptic drugs (AED).However, 30% of this patient group, (Eadie et al., 2012), are unable toobtain seizure freedom from the AED that are available and as such aretermed as suffering from intractable or “treatment-resistant epilepsy”(TRE).

Intractable or treatment-resistant epilepsy was defined in 2009 by theInternational League Against Epilepsy (ILAE) as “failure of adequatetrials of two tolerated and appropriately chosen and used AED schedules(whether as monotherapies or in combination) to achieve sustainedseizure freedom” (Kwan et al., 2009).

Individuals who develop epilepsy during the first few years of life areoften difficult to treat and as such are often termedtreatment-resistant. Children who undergo frequent seizures in childhoodare often left with neurological damage which can cause cognitive,behavioral and motor delays.

Childhood epilepsy is a relatively common neurological disorder inchildren and young adults with a prevalence of approximately 700 per100,000. This is twice the number of epileptic adults per population.

When a child or young adult presents with a seizure, investigations arenormally undertaken in order to investigate the cause. Childhoodepilepsy can be caused by many different syndromes and genetic mutationsand as such diagnosis for these children may take some time.

The main symptom of epilepsy is repeated seizures. In order to determinethe type of epilepsy or the epileptic syndrome that a patient issuffering from an investigation into the type of seizures that thepatient is experiencing is undertaken. Clinical observations andelectroencephalography (EEG) tests are conducted and the type(s) ofseizures are classified according to the ILEA classification describedbelow and in FIG. 1.

The International classification of seizure types proposed by the ILAEwas adopted in 1981 and a revised proposal was published by the ILAE in2010 and has not yet superseded the 1981 classification. FIG. 1 isadapted from the 2010 proposal for revised terminology and includes theproposed changes to replace the terminology of partial with focal. Inaddition the term “simple partial seizure” has been replaced by the term“focal seizure where awareness/responsiveness is not impaired” and theterm “complex partial seizure” has been replaced by the term “focalseizure where awareness/consciousness is impaired”.

From FIG. 1 it can be seen that Generalised seizures, where the seizurearises within and rapidly engages bilaterally distributed networks, canbe split into six subtypes: Tonic-Clonic (grand mal) seizures; Absence(petit mal) Seizures; Clonic Seizures; Tonic Seizures; Atonic Seizuresand Myoclonic Seizures.

Focal (partial) seizures where the seizure originates within networkslimited to only one hemisphere, are also split into sub-categories. Herethe seizure is characterized according to one or more features of theseizure, including aura, motor, autonomic and awareness/responsiveness.Where a seizure begins as a localized seizure and rapidly evolves to bedistributed within bilateral networks this seizure is known as abilateral convulsive seizure, which is the proposed terminology toreplace Secondary Generalized Seizures (generalized seizures that haveevolved from focal seizures and are no longer remain localized).

Focal seizures where the subject's awareness/responsiveness is alteredare referred to as focal seizures with impairment and focal seizureswhere the awareness or responsiveness of the subject is not impaired arereferred to as focal seizures without impairment.

Atonic seizures involve the loss of muscle tone, causing the person tofall to the ground. These are sometimes called ‘drop attacks’ and areusually brief (less than 15 seconds). Atonic seizures can occur withoutwarning while standing, sitting and walking and the patient oftensuffers from trauma due to falling.

Atonic seizures are often associated with Lennox-Gastaut Syndrome butalso occur, and may be symptomatic of other types of epileptic syndromesincluding: Tuberous Sclerosis Complex; Dravet Syndrome; Doose Syndrome;Aicardi syndrome; CDKL5 and Dup15q.

Epileptic syndromes often present with many different types of seizureand identifying the types of seizure that a patient is suffering from isimportant as many of the standard AED's are targeted to treat or areonly effective against a given seizure type/sub-type.

One such childhood epilepsy syndrome is Lennox-Gastaut syndrome.Lennox-Gastaut syndrome is a severe form of epilepsy. Seizures usuallybegin before the age of 4. Seizure types, which vary among patients,include tonic (stiffening of the body, upward deviation of the eyes,dilation of the pupils, and altered respiratory patterns), atonic (briefloss of muscle tone and consciousness, causing abrupt falls), atypicalabsence (staring spells), and myoclonic (sudden muscle jerks). There maybe periods of frequent seizures mixed with brief, relativelyseizure-free periods.

Most children with Lennox-Gastaut syndrome experience some degree ofimpaired intellectual functioning or information processing, along withdevelopmental delays, and behavioural disturbances.

Lennox-Gastaut syndrome can be caused by brain malformations, perinatalasphyxia, severe head injury, central nervous system infection andinherited degenerative or metabolic conditions. In 30-35 percent ofcases, no cause can be found.

The first line treatment for atonic seizures, including the treatment ofatonic seizures in patients with Lennox-Gastaut syndrome usuallycomprises a broad spectrum AED, such as sodium valproate often incombination with lamotrigine. Other AED that may be considered includerufinamide, felbamate, clobazam and topiramate.

AED such as carbamezapine, gabapentin, oxcarbazepine, pregabalin,tiagabineor and vigabatrin are contra-indicated in atonic seizures.

Common AED defined by their mechanisms of action are described in thefollowing tables:

TABLE 1 Examples of narrow spectrum AED Narrow- spectrum AED MechanismIndication Phenytoin Sodium channel Complex partial Tonic-clonicPhenobarbital GABA/Calcium channel Partial seizures Tonic-clonicCarbamazepine Sodium channel Partial seizures Tonic-clonic Mixedseizures Oxcarbazepine Sodium channel Partial seizures Tonic-clonicMixed seizures Gabapentin Calcium channel Partial seizures Mixedseizures Pregabalin Calcium channel Adjunct therapy for partial seizureswith or without secondary generalisation Lacosamide Sodium channelAdjunct therapy for partial seizures Vigabatrin GABA Secondarilygeneralized tonic- clonic seizures Partial seizures Infantile spasms dueto West syndrome

TABLE 2 Examples of broad spectrum AED Broad- spectrum AED MechanismIndication Valproic acid GABA/Sodium channel First-line treatment fortonic- clonic seizures, absence seizures and myoclonic seizuresSecond-line treatment for partial seizures and infantile spasms.Intravenous use in status epilepticus Lamotrigine Sodium channel Partialseizures Tonic-clonic Seizures associated with Lennox-Gastaut syndromeTopiramate GABA/Sodium channel Seizures associated with Lennox-Gastautsyndrome Zonisamide GABA/Calcium/Sodium Adjunctive therapy in adultschannel with partial-onset seizures Infantile spasm Mixed seizureLennox-Gastaut syndrome Myoclonic Generalised tonic-clonic seizureLevetiracetam Calcium channel Partial seizures Adjunctive therapy forpartial, myoclonic and tonic-clonic seizures Clonazepam GABA Typical andatypical absences Infantile myoclonic Myoclonic seizures Akineticseizures Atonic seizures Rufinamide Sodium channel Adjunctive treatmentof partial seizures associated with Lennox-Gastaut syndrome

TABLE 3 Examples of AED used specifically in childhood epilepsy AEDMechanism Indication Clobazam GABA Adjunctive therapy in complex partialseizures Status epilepticus Myoclonic Myoclonic-absent Simple partialComplex partial Absence seizures Lennox-Gastaut syndrome StiripentolGABA Severe myoclonic epilepsy in infancy (Dravet syndrome)

From these tables it can be seen that there is only one drug currentlyapproved for use in the treatment of atonic seizures, namely clonazepam.This medication works by the GABA mechanism.

Over the past forty years there have been a number of animal and humanstudies on the use of the non-psychoactive cannabinoid cannabidiol (CBD)to treat seizures.

A study in 1978 provided 200 mg/day of pure CBD to four adult patients,two of the four patients became seizure free, whereas in the remainder,seizure frequency was unchanged (Mechoulam and Carlini, 1978).

Cunha et al. reported that administration of CBD to eight adult patientswith generalized epilepsy resulted in a marked reduction of seizures in4 of the patients (Cunha et al., 1980) and Consroe et al., (1982)determined that CBD was able to prevent seizures in mice afteradministration of pro-convulsant drugs or an electric current.

In contrast to the studies described above, an open label study reportedthat 200 mg/day of pure CBD was ineffective in controlling seizures intwelve institutionalized adult patients (Ames and Cridland, 1986).

All of the studies described above focused on the treating subjectssuffering from generalised epilepsy and did not look at the treatment ofspecific seizure sub-types.

More recently, WO 2011/001169 describes the use of CBD in the treatmentof focal seizures, WO 2012/093255 describes the use of CBD incombination with standard anti-epileptic drugs in the treatment ofepilepsy and WO 2013/045891 describes a composition comprising CBD andCBDV for use in the treatment of epilepsy.

In November 2013 the company GW Pharmaceuticals made a press release tostate that they were intending to treat Dravet Syndrome with CBD as ithad received orphan drug designation. The company made a further pressrelease in February 2014 that that they were intending to treatLennox-Gastaut Syndrome with CBD as it had also received orphan drugdesignation.

Again the rationale was to treat a disease as opposed to the type ofseizure that the subject experienced.

It has additionally been suggested that cannabis which is enriched inCBD may be efficacious in the treatment of epilepsy. A case study of achild with Lennox-Gastaut syndrome showed improvement in seizurefrequency after treatment with CBD in an oily solution was reported in2005 (Pelliccia et al. 2005).

Porter and Jacobson (2013) report on a parent survey conducted via aFacebook group which explored the use of cannabis which was enrichedwith CBD in children with treatment-resistant epilepsy. It was foundthat sixteen of the 19 parents surveyed reported an improvement in theirchild's epilepsy. The children surveyed for this paper were all takingcannabis that was purported to contain CBD in a high concentrationalthough the amount of CBD present and the other constituents includingTHC were not known for many of the cases. Indeed, whilst CBD levelsranged from 0.5 to 28.6 mg/kg/day (in those extracts tested), THC levelsas high as 0.8 mg/kg/day were reported. Providing children with TRE witha cannabis extract that comprises THC, which has been described as apro-convulsant (Consroe et al., 1977), at a potentially psychoactivedose of 0.8 mg/kg/day, is a concern.

In addition a paper published in June 2014 describes the use of ahigh-CBD strain to treat a patient with Dravet Syndrome; the patient'sseizure frequency was stated to be reduced by the treatment (Maa et al.2014).

A document published after the priority application was filed disclosesthe use of CBD in the treatment of refractory epilepsy in the treatmentof Tuberous Sclerosis Complex in patients having focal onset seizures(Geffrey et al., 2014).

Whilst the potential of cannabis and the cannabinoids, including CBD, totreat epilepsy has been rekindled, to date there has been little in theway of real data to support its efficacy in patients.

The applicant has found that CBD shows significant efficacy in reducingatonic seizures, by greater than 50% in a large proportion, namely 63%,of patients. By way of comparison the proportion of patients benefittingfrom a greater than 50% reduction in total seizures was significantlyless, (46%), in all subjects treated.

It is additionally worth noting that the patients being treated weretreatment resistant to existing AED and so consequently these figuresare even the more remarkable.

BRIEF SUMMARY OF THE DISCLOSURE

In accordance with a first aspect of the present invention there isprovided cannabidiol (CBD) for use in the treatment of atonic seizures.

Preferably the atonic seizures are treatment-resistant.

Preferably the atonic seizures associated with Lennox-Gastaut Syndrome;Tuberous Sclerosis Complex; Dravet Syndrome; Doose Syndrome; Aicardisyndrome, CDKL5 or Dup15q.

In one embodiment the CBD is for use in combination with one or moreconcomitant anti-epileptic drugs (AED).

In a further embodiment the CBD is present as a highly purified extractof cannabis which comprises at least 95% (w/w) CBD, more preferably 98%(w/w) CBD. Preferably the extract comprises less than 0.15% THC. Morepreferably the extract further comprises up to 1% CBDV.

In an alternative embodiment the wherein the CBD is present as asynthetic compound.

In a further embodiment of the invention the one or more AED is selectedfrom the group consisting of: clobazam; clonazepam, levetiracetam;topiramate; stiripentol; phenobarbital; lacsamide; valproic acid;zonisamide; perampanel; and fosphenytoin.

Preferably the number of different anti-epileptic drugs that are used incombination with the CBD is reduced. Alternatively the dose of the oneor more anti-epileptic drugs that are used in combination with the CBDis reduced.

Preferably the dose of CBD is greater than 5 mg/kg/day.

In accordance with a second aspect of the present invention there isprovided a method of treating atonic seizures comprising administeringcannabidiol (CBD) to a subject.

In accordance with a third aspect of the present invention there isprovided a composition for use in the treatment of atonic seizurescharacterised by atonic seizures comprising cannabidiol (CBD), asolvent, a co-solvent, a sweetener, and a flavouring.

Preferably the solvent is sesame oil, the co-solvent is ethanol, thesweetener is sucralose, the flavouring is strawberry flavour and the CBDis present at a concentration of between 25/mg/ml and 100 mg/ml.

More preferably the composition comprises cannabidiol (CBD) at aconcentration of between 25 to 100 mg/ml, ethanol at a concentration of79 mg/ml, sucralose at a concentration of 0.5 mg/ml, strawberryflavouring at a concentration of 0.2 mg/ml and sesame q.s. to 1.0 ml.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the ILEA 2010 proposal for revised terminology fororganization of seizures and epilepsies.

DEFINITIONS

Definitions of some of the terms used to describe the invention aredetailed below:

The cannabinoids described in the present application are listed belowalong with their standard abbreviations.

TABLE 4 Cannabinoids and their abbreviations CBD Canna- bidiol

CBDA Canna - bidiolic acid

CBDV Cannabi- divarin

CBDVA Cannabi- divarinic acid

THC Tetrahydro- cannabinol

The table above is not exhaustive and merely details the cannabinoidswhich are identified in the present application for reference. So farover 60 different cannabinoids have been identified and thesecannabinoids can be split into different groups as follows:Phytocannabinoids; Endocannabinoids and Synthetic cannabinoids (whichmay be novel cannabinoids or synthetically produced phytocannabinoids orendocannabinoids).

“Phytocannabinoids” are cannabinoids that originate from nature and canbe found in the cannabis plant. The phytocannabinoids can be isolatedfrom plants to produce a highly purified extract or can be reproducedsynthetically.

“Highly purified cannabinoids” are defined as cannabinoids that havebeen extracted from the cannabis plant and purified to the extent thatother cannabinoids and non-cannabinoid components that are co-extractedwith the cannabinoids have been removed, such that the highly purifiedcannabinoid is greater than or equal to 95% (w/w) pure.

“Synthetic cannabinoids” are compounds that have a cannabinoid orcannabinoid-like structure and are manufactured using chemical meansrather than by the plant.

Phytocannabinoids can be obtained as either the neutral (decarboxylatedform) or the carboxylic acid form depending on the method used toextract the cannabinoids. For example it is known that heating thecarboxylic acid form will cause most of the carboxylic acid form todecarboxylate into the neutral form.

“Treatment-resistant epilepsy” (TRE) or “intractable epilepsy” isdefined as per the ILAE guidance of 2009 as epilepsy that is notadequately controlled by trials of one or more AED.

“Childhood epilepsy” refers to the many different syndromes and geneticmutations that can occur to cause epilepsy in childhood. Examples ofsome of these are as follows: Dravet Syndrome; Myoclonic-AbsenceEpilepsy; Lennox-Gastaut syndrome; Generalized Epilepsy of unknownorigin; CDKL5 mutation; Aicardi syndrome; bilateral polymicrogyria;Dup15q; SNAP25; and febrile infection related epilepsy syndrome (FIRES);benign rolandic epilepsy; juvenile myoclonic epilepsy; infantile spasm(West syndrome); and Landau-Kleffner syndrome. The list above isnon-exhaustive as many different childhood epilepsies exist.

“Atonic Seizures” are defined as a convulsive type of epileptic seizurewhich causes the muscles to relax and the patient to flop or fall.

“Mixed seizures” are defined as the existence of both generalised andfocal seizures in the same patient.

The terms “50% responder” and “50% reduction in seizure” are both termsused in clinical studies. In the present application the terms definethe percentage of subjects that experienced a greater than or equal to50% reduction in the number of seizures during treatment with CBD incomparison to the number experienced during the baseline period beforethe CBD was administered.

DETAILED DESCRIPTION

Preparation of Highly Purified CBD Extract

The following describes the production of the highly-purified (>98% w/w)cannabidiol extract which has a known and constant composition which wasused for the expanded access trials described in Examples below.

In summary the drug substance used in the trials is a liquid carbondioxide extract of high-CBD containing chemotypes of Cannabis sativa L.which had been further purified by a solvent crystallization method toyield CBD. The crystallisation process specifically removes othercannabinoids and plant components to yield greater than 95% CBD w/w,typically greater than 98% w/w.

The Cannabis sativa L. plants are grown, harvested, and processed toproduce a botanical extract (intermediate) and then purified bycrystallization to yield the CBD (drug substance).

The plant starting material is referred to as Botanical Raw Material(BRM); the botanical extract is the intermediate; and the activepharmaceutical ingredient (API) is CBD, the drug substance.

Both the botanical starting material and the botanical extract arecontrolled by specifications. The drug substance specification isdescribed in Table 5 below.

TABLE 5 CBD Specification Test Test Method Limits Appearance VisualOff-white/pale yellow crystals Identification A HPLC-UV Retention timeof major peak corresponds to certified CBD Reference StandardIdentification B GC-FID/MS Retention time and mass spectrum of majorpeak corresponds to certified CBD Reference Standard Identification CFT-IR Conforms to reference spectrum for certified CBD ReferenceStandard Identification D Melting 65-67° C. Point Identification ESpecific Conforms with certified CBD Optical Reference Standard; −110°Rotation to −140° (in 95% ethanol) Total Purity Calculation ≥98.0%Chromatographic Purity HPLC-UV ≥98.0% 1 Chromatographic Purity GC-FID/MS≥98.0% 2 Other Cannabinoids: HPLC-UV CBDA NMT 0.15% w/w CBDV NMT 1.0%w/w Δ⁹ THC NMT 0.15% w/w CBD-C4 NMT 0.5% w/w Residual Solvents: GCAlkane NMT 0.5% w/w Ethanol NMT 0.5% w/w Residual Water Karl Fischer NMT1.0% w/w NMT—Not more than

The purity of the CBD drug substance achieved is greater than 98%. Theother cannabinoids which may occur in the extract are: CBDA, CBDV,CBD-C4 and THC.

Distinct chemotypes of Cannabis sativa L. plant have been produced tomaximize the output of the specific chemical constituents, thecannabinoids. One type of plant produces predominantly CBD. Only the(−)-trans isomer occurs naturally, furthermore during purification thestereochemistry of CBD is not affected.

Production of the Intermediate

An overview of the steps to produce a botanical extract, theintermediate, are as follows:

1. Growing

2. Decarboxylation

3. Extraction No. 1—using liquid CO₂

4. Extraction No. 2—‘winterization’ using ethanol

5. Filtration

6. Evaporation

High CBD chemovars were grown, harvested and dried and stored in a dryroom until required. The botanical raw material (BRM) was finely choppedusing an Apex mill fitted with a 1 mm screen. The milled BRM was storedin a freezer for up to 3 months prior to extraction.

Decarboxylation of CBDA to CBD was carried out using a large Heraeustray oven. The decarboxylation batch size in the Heraeus isapproximately 15 Kg. Trays were placed in the oven and heated to 105°C.; the BRM took 96.25 minutes to reach 105° C. Held at 105° C. for 15Minutes. Oven then set to 150° C.; the BRM took 75.7 minutes to reach150° C.; BRM held at 150° C. for 130 Minutes. Total time in the oven was380 Minutes, including 45 minutes cooling and 15 Minutes venting.

Extraction No 1 was performed using liquid CO₂ at 60 bar/10° C. toproduce botanical drug substance (BDS) which was used forcrystallisation to produce the test material.

The crude CBD BDS was winterised in Extraction No 2 under standardconditions (2 volumes of ethanol at minus 20° C. for around 50 hours).The precipitated waxes were removed by filtration and the solventevaporated using the rotary evaporator (water bath up to 60° C.) toyield the BDS.

Production of the Drug Substance

The manufacturing steps to produce the drug substance from theintermediate botanical extract are as follows:

1. Crystallization using C5-C12 straight chain or branched alkane

2. Filtration

3. Optional recrystallization from C5-C12 straight chain or branchedalkane

4. Vacuum drying

Intermediate botanical extract (12 kg) produced using the methodologyabove was dispersed in C5-C12 straight chain or branched alkane (9000ml, 0.75 vols) in a 30 litre stainless steel vessel.

The mixture was manually agitated to break up any lumps and the sealedcontainer then placed in a freezer for approximately 48 hours.

The crystals were isolated by vacuum filtration, washed with aliquots ofcold C5-C12 straight chain or branched alkane (total 12000 ml), anddried under a vacuum of <10 mb at a temperature of 60° C. until drybefore submitting the drug substance for analysis. The dried product wasstored in a freezer at minus 20° C. in a pharmaceutical grade stainlesssteel container, with FDA food grade approved silicone seal and clamps.

Production of the Drug Product

The drug product is presented as an oral solution. The oral solutionpresentation contains 25 mg/ml or 100 mg/ml CBD, with the excipientssesame oil, ethanol, sucralose and flavouring. Two product strengths areavailable to allow dose titration across a wide dose range.

The 25 mg/ml solution is appropriate at lower doses and the 100 mg/mlsolution at higher doses.

The drug product formulation is as described in Table 6 below:

TABLE 6 Drug Product specification Reference Qualitative to QualityComponent Composition Function Standard Cannabidiol (CBD) 25 mg/ml or100 mg/ml Active In-house Anhydrous ethanol 79.0 mg/ml* Excipient Ph.Eur. Sucralose 0.5 mg/ml Sweetener In-house Strawberry 0.2 mg/mlFlavouring In-house flavouring Sesame oil q.s to 1.0 ml Excipient Ph.Eur.

The drug substance, CBD is insoluble in water. Sesame oil was selectedas an excipient to solubilize the drug substance.

A sweetener and fruit flavouring are required to improve palatability ofthe sesame oil solution.

Ethanol was required to solubilize the sweetener and the flavouring.

The composition can be substantially equivalent, by which is meant thefunctional ingredients can vary from the qualitative compositionspecified in Table 6 by an amount of up to 10%.

Example 1 below describes the use of a highly purified cannabis extractcomprising cannabidiol (CBD) in an expanded access treatment program inchildren with TRE.

Example 1: Efficacy of Cannabidiol Reducing Atonic Seizures in Childrenand Young Adults with Intractable Epilepsy

Materials and Methods

Of 137 children and young adults with severe, childhood onsettreatment-resistant epilepsy (TRE), twenty-seven suffered from epilepsythat was characterised by atonic seizures. These subjects were testedwith a highly purified extract of cannabidiol (CBD) obtained from acannabis plant. All subjects presented with atonic type seizures, oftenin addition to other seizures. The participants in the study were partof an expanded access compassionate use program for CBD.

The epileptic syndromes that these patients suffered from were asfollows: Lennox-Gastaut Syndrome; Tuberous Sclerosis Complex; DravetSyndrome; Doose Syndrome; Aicardi syndrome, CDKL5 and Dup15q.

All patients entered a baseline period of 4 weeks whenparents/caregivers kept prospective seizure diaries, noting allcountable seizure types.

The patients then received a highly purified CBD extract (greater than98% CBD w/w) in sesame oil, of known and constant composition, at a doseof 5 mg/kg/day in addition to their baseline anti-epileptic drug (AED)regimen.

The daily dose was gradually increased by 2 to 5 mg/kg increments untilintolerance occurred or a maximum dose of 25 mg/kg/day was achieved.

Patients were seen at regular intervals of 2-4 weeks. Laboratory testingfor hematologic, liver, kidney function, and concomitant AED levels wasperformed at baseline, and after 4 weeks of CBD therapy.

All patients were taking at least two concomitant anti-epileptic drugs.These included clobazam; levetiracetam; topiramate; stiripentol;phenobarbital; lacsamide; valproic acid; zonisamide. The average numberof concomitant antiepileptic drugs being taken was 2.7. The majoritytook either clobazam and/or valproic acid.

Results

There were 27 children and young adult patients all of whom sufferedfrom atonic seizures received treatment with CBD for at least 12 weeks.

A summary of the 50% responders, based on 12 weeks of treatment aresummarized in Table 7 below.

TABLE 7 Summary of 50% responders after 12 weeks of treatment for atonicseizures Atonic seizures Total seizures (n = 27) (n = 137) >50%reduction in 63% (n = 17) 46% (n = 63) seizures <50% reduction in 37% (n= 10) 54% (n = 74) seizures

Table 7 shows that after 3 months of therapy, a remarkable 63% ofpatients had an equal to or greater than >50% reduction in atonicseizures, these data infer that the CBD is very effective at reducingthis type of seizure.

CONCLUSIONS

These data indicate that CBD significantly reduces the number of atonicseizures in a high proportion of patients that do not respond well toexisting AED.

It was surprising that in this group of patients which aretreatment-resistant such a high number were able to gain an effect. Thefact that nearly two thirds of the patients (63%) benefitted from atleast a fifty percent reduction in the number of atonic seizures thatthey suffered from was remarkable.

Furthermore when these data are compared to the other sub-types ofgeneralised seizure, it can clearly be seen that CBD was able toselectively reduce the occurrence of atonic seizures. Table 8 belowdetails these findings.

TABLE 8 Summary of 50% responders after 12 weeks of treatment for allseizure sub-types Tonic- Atonic Tonic clonic Clonic Myoclonic Absenceseizures seizures seizures seizures seizures seizures (n = 27) (n = 45)(n = 65) (n = 8) (n = 30) (n = 28) >50% 63% 49% 43% 50% 43% 64%reduction (n = 17) (n = 22) (n = 28) (n = 4) (n = 13) (n = 18) inseizures <50% 37% 51% 37% 50% 57% 36% reduction (n = 10) (n = 23) (n =37) (n = 4) (n = 17) (n = 10) in seizures

From Table 8 it can be seen that when the number of atonic seizuresrecorded is compared with other generalised seizure types such as tonicseizures (49% of patients experienced a greater than 50% reduction inseizure), tonic-clonic seizures (43% of patients experienced a greaterthan 50% reduction in seizure), and myoclonic seizures (43% of patientsexperienced a greater than 50% reduction in seizure) the fact thatnearly two thirds (63%) of patients experiencing atonic seizures had agreater than 50% reduction in the number of seizures that occurred isvery surprising.

REFERENCES

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The invention claimed is:
 1. A method of treating seizures in a patientwith Lennox-Gastaut syndrome or Dravet syndrome, comprising orallyadministering to the patient in need thereof cannabidiol (CBD), whereinthe CBD has a purity of at least 95% (w/w), and wherein the CBD isadministered in a composition, comprising: (i) CBD at a concentrationranging from about 22.5 mg/mL and about 110 mg/mL; (ii) ethanol at aconcentration ranging from about 71.1 mg/mL to about 86.9 mg/mL; (iii) asweetener at a concentration ranging from about 0.45 mg/mL to about 0.55mg/mL; (iv) flavoring at a concentration ranging from about 0.18 mg/mLto about 0.22 mg/mL; and (v) a solvent.
 2. The method according to claim1, wherein the sweetener is sucralose.
 3. The method according to claim1, wherein the flavoring is strawberry flavor.
 4. The method accordingto claim 1, wherein the composition comprises from about 25 mg/mL toabout 100 mg/mL of CBD.
 5. The method of claim 1, wherein thecomposition comprises about 79 mg/mL of ethanol.
 6. The method of claim2, wherein the composition comprises about 0.5 mg/mL of sucralose. 7.The method of claim 3, wherein the composition comprises about 0.2 mg/mLof strawberry flavoring.
 8. The method of claim 1, wherein thecomposition comprises about 100 mg/mL of CBD that has a purity of atleast 98% (w/w).
 9. The method of claim 1, wherein the compositioncomprises: (i) about 90 mg /mL to about 110 mg/mL of CBD that has apurity of at least 98% (w/w); (ii) about 71.1 mg/mL to about 86.9 mg/mLof ethanol; (iii) about 0.45 mg/mL to about 0.55 mg/mL of sucralose;(iv) about 0.18 mg/mL to about 0.22 mg/mL of strawberry flavoring; and(v) sesame oil q.s. to about 1.0 ml.
 10. An oral pharmaceuticalcomposition comprising: (i) cannabidiol (CBD) at a concentration ofbetween about 22.5 mg/ml and about 110 mg/ml, (ii) ethanol at aconcentration of about 71.1 mg/ml to about 86.9 mg/ml, (iii) sweetenerat a concentration of about 0.45 mg/ml to about 0.55 mg/ml, (iv)flavoring at a concentration of about 0.18 mg/ml to about 0.22 mg/ml,and (v) sesame oil.
 11. The oral pharmaceutical composition of claim 10,wherein the CBD is at a concentration of about 100 mg/mL±10%.
 12. Theoral pharmaceutical composition of claim 10, wherein the CBD has apurity of at least about 95% (w/w).
 13. The oral pharmaceuticalcomposition of claim 10, wherein the CBD has a purity of at least about98% (w/w).
 14. The oral pharmaceutical composition of claim 10, whereinthe sweetener is sucralose.
 15. The oral pharmaceutical composition ofclaim 10, wherein the flavoring is strawberry flavoring.
 16. The oralpharmaceutical composition of claim 10, wherein: (i) the CBD is at aconcentration of between about 90 mg/ml and about 110 mg/ml; (ii)ethanol is at a concentration of about 71.1 mg/ml to about 86.9 mg/mL;(iii) the sweetener is at a concentration of about 0.45 mg/ml to about0.55 mg/ml; (iv) the flavoring is at a concentration of about 0.18 mg/mlto about 0.22 mg/ml; and (v) the sesame oil, q.s. to about 1.0 ml. 17.The composition of claim 16, wherein the CBD has a purity of at leastabout 95% (w/w).
 18. The composition of claim 16, wherein the CBD has apurity of at least about 98% (w/w).
 19. The method according to claim 1,wherein the solvent is sesame oil.
 20. An oral pharmaceuticalcomposition, comprising: (i) CBD at a concentration of between about22.5 mg/ml and about 110 mg/ml, wherein the CBD has a purity of at leastabout 95% (w/w); (ii) ethanol is at a concentration of about 71.1 mg/mlto about 86.9 mg/mL; (iii) the sweetener is at a concentration of about0.45 mg/ml to about 0.55 mg/ml; (iv) the flavoring is at a concentrationof about 0.18 mg/ml to about 0.22 mg/ml; and (v) sesame oil.
 21. Theoral pharmaceutical composition of claim 19, wherein the compositioncomprises: (i) about 90 mg /mL to about 110 mg/mL of CBD that has apurity of at least 98% (w/w); (ii) about 71.1 mg/mL to about 86.9 mg/mLof ethanol; (iii) about 0.45 mg/mL to about 0.55 mg/mL of sucralose; and(iv) about 0.18 mg/mL to about 0.22 mg/mL of strawberry flavoring.